Oral treatment with ambroxol — an investigational chaperone therapy — plus enzyme replacement therapy (ERT) was found to be safe over a course of 4.5 years, and helped partially restore glucocerebroside activity in people with neuronopathic forms of Gaucher disease (GD), a small trial suggests.
The trial, in four patients in Korea, also showed that ambroxol could halt neurological worsening, the researchers said.
Although the combination of ambroxol and the ERT Abcertin (imiglucerase) — sold as Cerezyme in the U.S. and Europe — initially worsened neurological symptoms, increasing the dose of ambroxol lessened these complications, leading to a marked reduction in the number of seizures.
The study, “Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy,” was published in the Journal of Medical Genetics.
ERT replaces the incorrectly formed beta-glucocerebrosidase, or GCase enzyme in people with Gaucher disease. A combination of ERT and substrate reduction therapy (SRT) — which reduces the toxic buildup of glucocerebroside — have been found to significantly ease systemic manifestations of GD, including blood disorders, spleen and liver enlargement, and skeletal disease.
But none of these therapies effectively address neurological problems in people with neuronopathic GD, namely types 2 and 3. This happens because lab-made enzymes in ERTs cannot cross the blood-brain barrier or BBB — a selective membrane between the blood and the brain — and SRT is not active against neurological manifestations.
Ambroxol has been proposed as a treatment for Gaucher patients with brain and spinal cord manifestations. It is a mucolytic (mucus thinner) agent used to treat respiratory diseases and often found in cough syrups.
The medication is being tested for GD as a chaperone therapy, because it binds to faulty GCase and helps it fold properly, which could restore its activity. Importantly, ambroxol is able to cross the BBB and reach the brain.
A pilot study in people with GD types 2 and 3 previously showed that high-dose oral ambroxol plus ERT was safe and increased GCase activity, while also easing neurological manifestations such as myoclonus (muscle jerks) and pupillary light reflex in the eye.
To assess the long-term safety and efficacy of this combination therapy, researchers now conducted a Phase 1/2 trial in four patients, ages 14 to 20, with neuronopathic Gaucher disease. The study was conducted at the Asan Medical Center in Seoul, Korea.
A beta-glucosidase leukocyte (BGL) test performed on blood samples confirmed that the combination therapy more than doubled GCcase activity over time. After 4.5 years, it had increased from a mean of 5.1% to 13.7% of normal enzyme activity — believed to be enough to prevent the harmful effects of GCase deficiency.
However, contrary to expectations, neurological manifestations aggravated during the first 2.5 years of treatment, with improvements only observed after the ambroxol dose was increased to 27 mg/kg/day.
Neurological progression of GD, measured with the modified severity scoring tool, or mSST, worsened from a mean of 2.3 to 15.1 after 2.5 years, improving to a score of 12.4 two years later.
Because the dose was increased by 3 mg/kg/day every 1–2 months, “the natural progression of neurological manifestations might have not been delayed by the therapeutic effects of ABX [ambroxol] during the early period of our study,” the researchers said.
At the study’s start, the frequency of myoclonic seizures — brief shock-like jerks of a muscle or group of muscles — was 8.5 per two weeks. The frequency of generalized tonic-clonic seizures — convulsions usually lasting 1-3 minutes, in which the person loses consciousness — was five per two weeks.
At 4.5 years, both types of seizures markedly decreased, to 1.25 myoclonic and 0.5 generalized tonic-clonic per two weeks. It is important to note, however, that the number of anti-epileptic therapies used by these patients also increased during this period.
At the end of treatment, major improvements also were noted in the participants’ ability to eat, dress, and move. Blood levels of lyso-Gb1, a biomarker for GD severity and progression, normalized with increasing doses of ambroxol.
The team noted significant drug-to-drug interactions between ambroxol and antiepileptic therapies. This affected ambroxol’s availability in the body, and requires monitoring when defining its optimal dose, the researchers said.
Long-term use of ambroxol plus Abcertin was generally well-tolerated and safe. Mild proteinuria, or protein in urine, as well as increased respiratory mucus production were the major adverse reactions observed.
Since proteinuria could signal problems in kidney function, “a careful follow-up is required,” the researchers said.
An important aspect was that the clinical severity of patients’ neurological manifestations at study start affected the clinical outcome of long-term treatment.
“Therefore, earlier administration of ABX [ambroxol], even before the progression of the neurological features (such as immediately on beginning of ERT in newly diagnosed [neuronopathic] GD patients), might have a greater value and achieve better results,” the scientists added.
The study was partly funded by ISU Abxis.
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